This invention relates generally to methods and compositions for reducing blood cholesterol levels in a subject.
According to recent information from the American Heart Association, an estimated 100,870,000 American adults have total cholesterol levels in the borderline-high risk range of 200 mg/dl to 239 mg/dl. There are 40,600,000 American adults living with high-risk cholesterol levels of 240 mg/dl or more. There are many risk factors that can indicate a propensity to have high levels of cholesterol, such as age, weight, health conditions such as diabetes, smoking, gender, race and ethnicity. Elevated blood cholesterol levels are associated with potentially deadly conditions of the heart and blood vessels, such as atherosclerosis, coronary artery insufficiency and stroke.
Atherosclerosis is the most common cause of death and serious morbidity in the Western world. Atherosclerosis is one of three morphologically distinct forms of arteriosclerosis. Arteriosclerosis is the hardening of the arteries due to their thickening and loss of elasticity. Atherosclerosis occurs when irregularly distributed lipid deposits form in the inner coating of the vessels of the elastic arteries, such as the aorta, carotid and iliac, or the large and medium-sized muscular arteries, such as the coronary and popliteal. These lipid deposits, called atheromatous plaques, cause fibrosis and calcification which leads to coronary heart disease and myocardial infarction. The plaques are comprised of cells, macrophages and other leukocytes, a connective tissue extra-cellular matrix and intracellular and extracellular lipid deposits. The progression of atherosclerosis can be slowed by reducing the plasma cholesterol and cholesterol LDL levels.
Hypercholesterolemia, or elevated blood cholesterol levels due to concentration of cholesterol in the cells and plasma, is also prevalent in the American population. Elevated total and LDL cholesterol levels are considered cardiovascular risk factors for coronary heart disease and myocardial infarction.
Cholesterol is the most abundant steroid in cell membranes and is essential to the growth and viability of cells. Cholesterol is classified as a lipid and forms lipoproteins, or complexes of cholesterol and protein. There are four major categories of lipoproteins: chylomicrons, very low density lipoproteins (VLDL), low density lipoproteins (LDL), and high density lipoproteins (HDL). Chylomicrons transport some dietary cholesterol and mostly triglycerides from the intestines to the adipose tissue (also known as fat) and the liver. VLDLs transport cholesterol and triglycerides made by the liver to adipose and other tissues. LDL is a byproduct consisting of apolipoprotein and cholesterol that remains after the fat cells have removed the triglycerides from the VLDL. LDLs transport cholesterol to the peripheral tissues (cells outside the liver and intestine) and regulate the endogenous cholesterol levels therein. LDL is often referred to as the xe2x80x9cbad cholesterolxe2x80x9d because high levels increase the risk of developing arteriosclerosis and hypercholesterolemia. HDL, known as the xe2x80x9cgood cholesterol,xe2x80x9d transports cholesterol from the peripheral tissues (and arterial walls) to the liver. HDLs operate as good cholesterol because they oppose LDLs. It is thought that high levels of HDL can reverse the negative effects of LDL activity. The primary site of cholesterol synthesis is in the liver, although some cholesterol is synthesized in the intestines. The liver""s function in this pathway is to remove the cholesterol from the blood. Plasma LDL is the primary source of cholesterol in peripheral tissues, which do not synthesize cholesterol de novo. LDL is taken into these cells via endocytosis at LDL receptor cites. The molecular genetics and cellular biology of the LDL receptor has been characterized by Goldstein and Brown. The LDL receptor is essential to cholesterol metabolism. When cholesterol is abundant inside the cell, there is no synthesis of LDL receptors, and thus cholesterol uptake from plasma cholesterol is blocked. The absence of the LDL receptor leads to hypercholesterolemia and atherosclerosis.
Free radical activity produces oxidized LDL. When macrophages take up oxidized LDL, they form foam cells which form the atheromatous plaques, described above, in the larger blood vessels. As these plaques cause fibrosis and calcification which lead to coronary heart disease and myocardial infarction, oxidized LDL levels are important indicators of patients with a disease propensity. Yamakoshi et al., xe2x80x9cProanthocyanidin-Rich Extract From Grape Aortic Atherosclerosis in Cholesterol-Fed Rabbits,xe2x80x9d Atherosclerosis, 142:139-149 (1999).
Wine has been shown to protect LDLs from lipid peroxidation. Specifically, red wine inhibits cell-mediated oxidation of LDL, whereas white wine does not seem to produce similar results. Rifici et al., xe2x80x9cRed Wine Inhibits the Cell-Mediated Oxidation of LDL and HDL,xe2x80x9d J. Am. Coll. Nutr., 18:137-143 (1999). This inhibition is believed to be caused by the antioxidant activity of proanthocyanidins responsible for the color of red wine. Nuttall et al., xe2x80x9cAn Evaluation of the Antioxidant Activity of a Standardized Grape Seed Extract,xe2x80x9d Leucoselect, J. Clin. Pharm. Ther., 23:385-389 (1998); see also, Yanakoshi et al., xe2x80x9cProanthocyanidin-Rich Extract from Grape Seeds Attenuates the Development of Aortic Atherosclerosis in Cholesterol-Fed Rabbits,xe2x80x9d Atherosclerosis, 142:139-149 (1999).
Proanthocyanidins comprise a group of polyphenolic bioflavonoids ubiquitously found in fruits and vegetables. They are the most common type of tannins found in fruits and vegetables, and are present in high amounts in the seeds and skins of grapes. Proanthocyanidins consist of polymers of the flavan-3-ol units (+)-catechin, (xe2x88x92)-epicatechin and (xe2x88x92)-epicatechin 3-O-gallate linked by C4-C8 or C4-C6 bonds. Some proanthocyanidins carry galloyl residues linked to the C-3 alcoholic function of the flavan-3-ol units. Proanthocyanidins have been the subject of considerable interest because of their broad pharmacologic activity and therapeutic potential. Chen et al., xe2x80x9cAntioxidative Activity of Natural Flavonoids is Governed by Number and Location of Their Aromatic Hydroxyl Groups,xe2x80x9d Chem. Phys. Lipids, 79:157-163 (1996). The biological and medicinal properties of the proanthocyanidins have been extensively reviewed, see, Rice-Evans et al., xe2x80x9cStructure-Antioxidant Activity Relationships of Flavonoids and Phenolic Acids,xe2x80x9d Free Rad. Biol. Med., 20:933-956 (1996). Purified proanthocyanidin compositions of this invention may be isolated or derived from a variety of plant sources according to known methods or may be produced synthetically. Proanthocyanidins are found in the fruit and seeds of a wide variety of fruit plants including but not limited to strawberry, blueberry and grapes. Proanthocyanidins are also present in large quantities in maritime pine bark, oak wood, black and green tea and in cocoa powder.
Chromium deficiency has also been linked to the development of atherosclerosis. Schroeder et al., xe2x80x9cChromium Deficiency as a Factor in Atherosclerosis,xe2x80x9d J. Chron. Dis., 23:123-142 (1970); Newman et al., xe2x80x9cSerum Chromium and Angiographically Determined Coronary Artery Disease,xe2x80x9d Clin. Chem., 24:341-544 (1978); Simonoff, xe2x80x9cChromium Deficiency and Cardiovascular Risk,xe2x80x9d Cardiovas. Res., 18:591-6 (1984); Simonoff et al., xe2x80x9cLow Plasma Chromium in Patients with Coronary Artery and Heart Disease,xe2x80x9d Biol. Trace Elem. Res., 6:431-439 (1984); Cote et al., xe2x80x9cHair Chromium Concentration and Coronary Artery Diseases in Canada, France, and Italy,xe2x80x9d Nutr. Res. Suppl. I, 356-359 (1985). Chromium (Cr) is necessary for insulin function as it is the biologically active component of glucose tolerance factor (GTF). GTF also contains nicotinic acid and is responsible for insulin activity. Oral chromium supplementation can lower cholesterol and triglyceride levels and increase HDL levels. For example, a double-blind study of thirty-four male athletes examined the effects of a dietary GTF-like supplement comprised of trivalent chromium nicotinic acid ingested daily for eight weeks. Lefavi et al., xe2x80x9cLipid-Lowering Effect of a Dietary Chromium (III)-Nicotinic Acid Complex in Male Athletes,xe2x80x9d Nutrition Research, 13:239-249 (1993). The supplement was accompanied by body building training while dietary conditions remained status quo. Serum lipid analyses were performed pre and post supplement after twelve hours of fasting and one hour of an athletic challenge. All pre-supplement values for insulin, glucose, total cholesterol, LDL, and HDL levels were with normal ranges. The data showed no change between groups regarding their insulin concentration and glucose tolerance, markers of insulin function. However, the lipid parameters reflected the lipid-lowering effects of this supplement similar to those observed for organic Cr compounds. Chromium""s influence on the various dyslipidemias is not consistent from study to study. Offenbacher et al., xe2x80x9cBeneficial Effect of Chromium-rich Yeast on Glucose Tolerance and Blood Lipids in Elderly Subjects,xe2x80x9d Diabetes, 29:919-925 (1980); Urberg et al., xe2x80x9cHypocholesterolemic Effects of Nicotinic Acid and Chromium Supplementation,xe2x80x9d J. Fam. Prac., 27:603-606 (1988); Roeback et al., xe2x80x9cEffects of Chromium Supplementation on Serum High-density Lipoprotein Cholesterol Levels in Men Taking Beta Blocker,xe2x80x9d Ann. Intern. Med., 115:917-924 (1991); Press et al., xe2x80x9cThe Effects of Chromium Picolinate on Serum Cholesterol and Apolipoprotein Fractions in Human Subjects,xe2x80x9d West. J. Med., 152:41-45 (1990); Abraham et al., xe2x80x9cThe Effects of Chromium Supplementation on Serum Glucose and Lipids in Patients With and Without Non-Insulin-Dependent Diabetes,xe2x80x9d Metab., 41:768-771 (1992). There is also conflicting data showing that chromium has little effect. Uusitupa et al., xe2x80x9cChromium Supplementation in Impaired Glucose Tolerance of Elderly: Effects on Blood Glucose, Plasma Insulin, C-peptide, and Lipid Levels,xe2x80x9d Br. J. Nutr., 68:209-216 (1992). The variance in the data may be explained by the variance in chromium forms (ligands), dosages, and patients"" age, gender, and health status.
Cholesterol levels are measured by withdrawing blood from a patient and performing standard blood chemistry tests thereon. Pharmaceuticals exist to treat elevated cholesterol levels but the majority cause significant side-effects, such as liver problems. For example, patients with hypercholesterolemia are usually started on one of three lipid-lowering therapeutic agents: (1) bile acid-binding resins, (2) niacin; or (3) 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. These drugs cause respectively: (1) constipation, gastric discomfort, nausea, hemorrhoidal bleeding; (2) arrhythmias, peptic ulcer disease, glucose intolerance, hepatic dysfunction; and (3) abnormal liver function and myositis. If these agents, normally prescribed as the first line of therapy are not successful, fibric acid derivatives like gemfibrozil are often administered. There are also side-effects with this class of drugs, such as lithogenicity of bile, nausea, abnormal liver functions and myositis. There remains a need for an effective method to reduce blood cholesterol levels without creating other medical complications. The present invention fulfills theses needs and provides further related advantages.
The present invention resides in methods and compositions to reduce cholesterol levels in a subject by administering an effective amount of proanthocyanidin and niacin-bound chromium (NBC).
Specifically, the invention provides for methods of reducing cholesterol levels in subjects that have been identified as having elevated cholesterol levels by administering proanthocyanidin and NBC in amounts effective to reduce cholesterol levels. The subject is preferably a human but could be a domestic animal or other subject with elevated cholesterol levels. While those of ordinary skill in the art can vary the daily dosages based upon the weight of the subject, the preferred daily dosage of proanthocyanidin is about 100-400 mg with the preferred daily dosage of NBC about 2-6 mg. The daily dosages of proanthocyanidin and NBC are preferably delivered orally, intravenously or by other method of delivery that one of skill in the art would employ. The proanthocyanidin is preferably grape seed proanthocyanidin extract (GSPE).
The invention also provides for compositions of proanthocyanidin and NBC. These compositions are preferably comprised of dosage units effective to reduce cholesterol levels, such as about 100-400 mg of proanthocyanidin per day and about 2-6 mg of NBC per day. A further preferred embodiment of the invention provides that proanthocyanidin is GSPE.
Other features and advantages of the present invention should become apparent from the following detailed description of the invention, which illustrate the principles of the invention.
An embodiment of the present invention involves administering proanthocyanidin and NBC to a subject as part of a suitable composition designed to be consumed by the subject. The method involves consumption of the composition by the subject, preferably as a regular treatment; e.g., daily. The composition contains an amount of proanthocyanidin and NBC sufficient to reduce blood cholesterol levels in the subject. The composition may be consumed by many known methods, such as orally or intravenously. As used herein xe2x80x9ccholesterolxe2x80x9d lowered by the practice of the invention includes total cholesterol, LDL, oxidative LDL, HDL, triglycerides combined or any of those components thereof individually.
Proanthocyanidin compositions such as those described herein are preferably proanthocyanidin from grapes, with grape skin and grape seeds being preferred sources. Purified proanthocyanidin may be obtained from methods such as those described in U.S. Pat. No. 5,912,363, the disclosure of which is incorporated herein by reference. A particularly preferred purified proanthocyanidin composition available as a standardized water-ethanol extract from red grape seeds for use according to this invention is available as a grape seed proanthocyanidin extract (GSPE) known under the ActiVin(copyright) brand available from InterHealth Nutraceuticals, Inc., Benicia, Calif. A compositional analysis of the ActiVin(copyright) brand grape seed proanthocyanidin extract shows a content comprising (by weight) 54% proanthocyanidin dimer, 13% proanthocyanidin trimer, 7% proanthocyanidin tetramer, and 6% monomer and other flavonoids. Because it is believed that the prophylactic and therapeutic activities of the purified proanthocyanidin compositions of the invention are primarily associated with the low molecular weight (DP2 to DP4) oligomeric content of the purified proanthocyanidin compounds preferred purified proanthocyanidin compositions comprise at least 50% and more preferably greater than 70% by weight DP2 to DP4 oligomeric proanthocyanidins.
The NBC compositions such as those described herein are also known as chromium-nicotinate GTF material, polynicotinate and are preferably available commercially as ChromMate(copyright) from InterHealth Nutraceuticals, Inc., Benicia, Calif. The ChromMate(copyright) brand of NBC is made from at least an alkali metal salt of nicotinic acid, a trivalent chromium salt and adjuvants. The composition and process for synthesizing the ChromMate(copyright) brand of NBC is disclosed in U.S. Pat. Nos. 5,194,615, 4,954,492 and 4,923,855, incorporated herein by reference. In general, a dissociable form of alkali metal, like an alkali metal hydroxide and nicotinic acid are combined to form the alkali metal salt of nicotinic acid. This salt is then reacted with trivalent chromium salt to yield the chromium-nicotinate GTF material (NBC). The ChromMate(copyright) brand of NBC can also be synthesized by reacting the alkali metal salt of nicotinic acid, obtained from other sources as known in the art, with the chromium salt. These reactions can be made with minimum temperature controls, from about 5xc2x0 C. to about 60xc2x0 C., and are usually performed in a polar solvent system, like an aqueous or alcohol solvent. The crude chromium-nicotinate can be washed, in water or other solvent in which the ChromMate(copyright) brand of NBC is insoluble, to remove any soluble compounds or dried at about 10xc2x0 C. to about 150xc2x0 C. at less than 100% relative humidity. ChromMate(copyright) brand of NBC is believed to be comprised of at least a substantial portion of a trinicotinic chromium complex, where 1 mg of ChromMate(copyright) brand of NBC contains 100 xcexcg of elemental chromium. A representative structure of ChromMate(copyright) brand of NBC is shown in U.S. Pat. No. 5,194,615.
According to an embodiment of the invention, a synergistic effect is achieved, when appropriate doses of GSPE and NBC (GSPE/NBC) are administered, that results in lower cholesterol levels than either GSPE or NBC alone or additively in the subject. The GSPE/NBC can be delivery by capsule, tablet or liquid or any other convenient form consistent with oral or injectable modes of administration. The composition can include inert ingredients or diluents, like starch or talc; other pharmaceutical ingredients of the sort often contained in over-the-counter analgesic remedies, such as caffeine, provided that adverse chemical reactions do not occur; and a barrier coating of a standard inert composition capable of separating the active ingredients. As one skilled in the art would appreciate, the GSPE/NBC can be administered by various methods, including orally or by injection.